Transforming growth factor-β-inducible early response gene 1 is a novel substrate for atypical protein kinase Cs

Alemu, Endalkachew Ashenafi; Sjøttem, Eva; Outzen, Heidi; Larsen, Kenneth Bowitz; Holm, Turid; Bjørkøy, Geir; Johansen, Terje

doi:10.1007/s00018-010-0541-1

Cited by 4 publications

(5 citation statements)

References 61 publications

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“…Using hierarchical multiple regression, we identified a model containing a significant three-way interaction between EGR1 mRNA, AR, and p53 expression associated with p21 expression (estimate [95% confidence interval (CI)] = 0.12 [0.03, 0.21]; p = 0.008; Table S5). This finding is in line with data we and others have presented, indicating that EGR1 and p53 upregulate p21 (Figures 6A-6C; Alemu et al, 2011; Parra et al, 2011; Riley et al, 2008) and that AR and p53 are transcriptionally and functionally linked (Table S2; Alimirah et al, 2007; Fu et al, 2003; Kang et al, 2009; Mooslehner et al, 2012; Shenket al, 2001; Zhu et al, 2016). However, this association does not necessarily imply a direct, functional relationship between these variables, and further mechanistic studies are required to understand the biological implications of this association.…”

Section: Discussionsupporting

confidence: 93%

The lncRNA SLNCR Recruits the Androgen Receptor to EGR1-Bound Genes in Melanoma and Inhibits Expression of Tumor Suppressor p21

et al. 2019

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Section: Discussionsupporting

confidence: 93%

The lncRNA SLNCR Recruits the Androgen Receptor to EGR1-Bound Genes in Melanoma and Inhibits Expression of Tumor Suppressor p21

et al. 2019

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“…Key functionally relevant, posttranslational modifications, including serine/threonine phosphorylation and ubiquitination of KLF10 have been previously observed (1,35). Several key pieces of data are important to consider within the context of this report.…”

Section: Epigenetic Regulation Of Foxp3mentioning

confidence: 77%

Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene

Xiong

Svingen

Sarmento

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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However, chromatin-mediated mechanisms that underlie these events in T regulatory cells remain to be fully characterized. Here, we report that inducibility of FOXP3, a key transcription factor for the development of T regulatory cells, depends upon Kruppel-like factor 10 (KLF10) interacting with two antagonistic histone-modifying systems. We utilized chromatin immunoprecipitation, genome-integrated reporter assays, and functional domain KLF10 mutant proteins, to characterize reciprocal interactions between this transcription factor and either the Sin3-histone deacetylase complex or the histone acetyltransferase, p300/CBP-associated factor (PCAF). We characterize a Sin3-interacting repressor domain on the NH2 terminus of KLF10, which works to limit the activating function of this transcription factor. Indeed, inactivation of this Sin3-interacting domain renders KLF10 able to physically associate with PCAF as to induce FOXP3 gene transcription. We show that this biochemical data derived from studying our genome-integrated reporter cell system are recapitulated in primary murine lymphocytes. Collectively, these results advance our understanding of how a single transcription factor, namely KLF10, functions as a toggle to integrate antagonistic signals regulating FOXP3 and, thus, immune activation.T regulatory cell; KLF10; PCAF; Sin3; FOXP3 FOXP3ϩ T REGULATORY (TREG) cells may develop outside the thymus, generally in response to transforming growth factor ␤ (TGF␤) and antigen to become critically important in intestinal immunologic homeostasis (adaptive Treg cells) (2,6,7,22,23,26). Dysregulation of the transcription factor FOXP3, a key initiator of the Treg differentiation and functional program, leads to immune dysregulation in both mice (scurfy mouse) and humans (IPEX-immune polyendocrinopathy enteritis and X-linked-syndrome) (16,38). While advances in T lymphocyte biology indicate the importance of TGF␤-induced activated T cells in both the induction (Th17 cells) and regulation (FOXP3ϩ Treg cells) of intestinal inflammation (3), the precise mechanistic events integrating the TGF␤ signal to intracellular pathways that function as inducers or regulators of inflammation are not fully defined.To identify these pathways, we recently characterized a role for a TGF␤-inducible Kruppel-like factor (KLF10) in silencing FOXP3 leading to enhanced colitis susceptibility, while providing mechanistic insights into how these functions require novel chromatin coupling events (40). These studies defined the importance of p300/CBP-associated factor (PCAF), a histone acetyltransferase (HAT) recruited by KLF10 to the FOXP3 transcriptional regulatory regions that are critical for the induction of this gene (40). In the experiments reported here, we build upon our previous discovery and demonstrate that KLF10 possesses the dual capacity to either positively or negatively regulate FOXP3 through its differential association with PCAF or the histone deacetylase binding protein Sin3, respectively. Collectively, these results increase our u...

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“…Through the use of TIEG1 domain expression constructs, we provide evidence that the C-terminal domain of TIEG1 is responsible for this transactivation function. The involvement of TIEG1's C-terminus in regulating Tcf/Lef enhancer element activity is not surprising since this region contains the zinc-finger DNA binding domain ( 1 , 5 ) and has previously been shown to be necessary for its transactivation potential ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

TIEG1 modulates β-catenin sub-cellular localization and enhances Wnt signaling in bone

Subramaniam

Cicek

Pitel

et al. 2017

Nucleic Acids Research

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We have previously demonstrated that TGFβ Inducible Early Gene-1 (TIEG1), also known as KLF10, plays important roles in mediating skeletal development and homeostasis in mice. TIEG1 has also been identified in clinical studies as one of a handful of genes whose altered expression levels or allelic variations are associated with decreased bone mass and osteoporosis in humans. Here, we provide evidence for the first time that TIEG1 is involved in regulating the canonical Wnt signaling pathway in bone through multiple mechanisms of action. Decreased Wnt signaling in the absence of TIEG1 expression is shown to be in part due to impaired β-catenin nuclear localization resulting from alterations in the activity of AKT and GSK-3β. We also provide evidence that TIEG1 interacts with, and serves as a transcriptional co-activator for, Lef1 and β-catenin. Changes in Wnt signaling in the setting of altered TIEG1 expression and/or activity may in part explain the observed osteopenic phenotype of TIEG1 KO mice as well as the known links between TIEG1 expression levels/allelic variations and patients with osteoporosis.

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Transforming growth factor-β-inducible early response gene 1 is a novel substrate for atypical protein kinase Cs

Cited by 4 publications

References 61 publications

The lncRNA SLNCR Recruits the Androgen Receptor to EGR1-Bound Genes in Melanoma and Inhibits Expression of Tumor Suppressor p21

The lncRNA SLNCR Recruits the Androgen Receptor to EGR1-Bound Genes in Melanoma and Inhibits Expression of Tumor Suppressor p21

Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene

TIEG1 modulates β-catenin sub-cellular localization and enhances Wnt signaling in bone

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